Lower back pain affects over 65 million people in the US alone, costing an estimated $100B annually. About 12 million of these cases arise from degeneration of the intervertebral disc (IVD) through trauma or natural aging. Additionally, disc degeneration results in compromised biomechanics with frequent progression to disrupted spinal dynamics, osteoarthritis and spinal instability. Many patients initially respond to conservative treatments such as anti-inflammatory medication but a significant number stop responding within a short period of time, at which point their main treatment option today is invasive surgery. Although commonly prescribed, moderately invasive surgical solutions such as discectomy and laminectomy, and more invasive solutions such as intervertebral fusion and total disc replacement have important problems and uncertainties surrounding their use. Clearly, a gap exists between marginally effective conservative treatments and invasive interventions. A solution is needed that can be applied minimally invasively while also directly addressing the root cause of the problem and allowing restoration of the biomechanics of an affected motion segment. This proposal describes the continued development of a suitable material to replace the nucleus pulposus of a degenerating disc, thereby restoring disc height and natural disc function. The existing principle technology is a novel method that forms a hydrogel from a liquid without a chemical reaction. Our specific aims will address the following requirements for an injectable poly(vinyl alcohol) (PVA) system as a nucleus pulposus (NP) replacement: (i) to exist as a liquid pre-gel that can be injected safely through an narrow gauge needle;(ii) to gel at body temperature and environment within minutes;(iii) to be space-filling and resist extrusion from annular tears, (iv) to survive at least 1 million cycles of dynamic loading with a peak load of 3 kN;and (v) be revisable to another treatment such as NP replacement, fusion or total disc replacement. To achieve this objective, we divide the proposed work into three Specific Aims: Specific Aim 1: We will investigate the effects of concentration, molecular weight, radiopacification and sterilization on the gelation kinetics and mechanical properties of a set of suitable hydrogels. Specific Aim 2: We will use a static extrusion model to screen the optimal hydrogel formulations developed in SA1, after gamma sterilization. Those formulations that pass the static extrusion will be subjected to dynamic extrusion for 100 thousand cycles. Specific Aim 3: We will use a simple IVD model under development that will allow the chosen formulation to be subjected to 1 million cycle fatigue testing of the material in physiologically relevant loading regimes. In addition, the successful formulations will also be fatigued in an IVD model with a deliberate annular defect. In addition, porcine Functional Spine Units (FSUs) will be tested to obtain early insight into changes in biomechanics due to the proposed procedure. PUBLIC HEALTH RELEVANCE: Chronic lower back pain, which afflicts 70% of the population at some point in their lives and costs the U.S. economy billions of dollars per year in worker's compensation and lost productivity, is often associated with degeneration of the intervertebral disc in the spine. The only treatment options available today are either pain medication or invasive surgical procedures involving joint fusion or total disc replacement. The research proposed here will further develop an innovative injectable hydrogel material that can replace or augment the existing intervertebral disc nucleus, and will hence restore the natural biomechanics of the joint and prevent or delay further degeneration of the spine.